Genotype to phenotype correlations in heritable pulmonary arterial hypertension

Abstract

Purpose: Autosomal dominant inheritance of germline mutations of the bone morphogenetic protein receptor type 2 (BMPR2) gene are a major risk factor for heritable pulmonary arterial hypertension. In fact, germline mutations in BMPR2 have been found in familial as well as in clinically sporadic forms of idiopathic pulmonary arterial hypertension. This study was performed to investigate the rate of BMPR2 gene mutations in cases with clinically familial or sporadic IPAH followed in a single center and to evaluate the correlation between genotype and phenotype. Methods: Tests for BMPR2 mutations were performed in 238 IPAH patients (22 with a family history of and 216 clinically sporadic). Clinical and haemodynamic characteristics were compared between BMPR2 mutation carriers (BMPR2+) and not-carriers (BMPR2-). Results: We identified mutations in 17 of 22 (77%) patients with a family history and in 38 of 216 (18%) with clinically sporadic IPAH patients. A BMPR2 mutation was also identified in 45 of 140 unaffected relatives (32%) who accepted to undergo the test. The mean age was 36±13 years in BMPR2+ (n=55) patients and 45±20 in BMPR2 – (n=183) (p<0.0001). The right atrial pressure was 8±4 mmHg in BMPR2+ and 7±5 mmHg in BMPR2- (p 0.4); mean pulmonary arterial pressure was 59±13 mmHg in BMPR2+ and 54±16 mmHg in BMPR2- (p 0.03); pulmonary vascular resistance was 15±7 WU in BMPR2+ and 12±8 WU in BMPR2- (p 0.019); cardiac index was 2.4±0.7 L/min/m2 in BMPR2+ and 2.7±0.9 L/min/m2 in BMPR2- (p 0.017). 6MWD was 445±97 meters in BMPR2+ and 395±121 meters in BMPR2- (p 0.002). Survival at 1, 3 and 5 years was 98%, 94% and 86% in BMPR2 – patients and 98%, 95% and 92% in BMPR2+ patients (P=0.9). Conclusion: The presence of a BMPR2 mutation in patients with IPAH (either clinically familial or sporadic) is associated with a younger age and a more severe hemodynamic impairment at diagnosis but not with a worse exercise capacity and prognosis. The younger age of BMPR2+ patients may explain the similar survival and exercise capacity despite a worse haemodynamics as compared with BMPR2- patients.